The pyrimidine scaffold is found in many natural products and also is a key heteroaryl used in many drug discovery projects. Various substituted pyrimidines have been used to synthesize a variety of protein kinase (e.g., JAK, MAP kinase, tyrosine kinases, and VEGF receptor) inhibitors for treatment or prevention of a wide range of diseases such as cancers, inflammatory bowel disease, or ocular neovascular diseases.
The synthesis of 2,4-disubstituted pyrimidines is facilitated, in part, due to the ready availability of reactive building blocks such as 2,4-dichloropyrimidine or 2-chloro-4-pyrimidone. Nucleophilic aromatic substitutions of 2,4-dichloropyrimidine occur preferentially at C-4 position. However, depending on the nucleophile, product mixtures arising from substitution at C-2 as well as C-4 positions are obtained; resulting in the difficult isolation of pure product. One can circumvent the mixture of products by using different starting materials such as 2-methylthio-4-pyrimidines or 4-thioalkyl-2-pyrimidones. However, this synthetic route also suffers from the drawback of an additional intermediate step between nucleophilic substitution reactions.